Field of the Invention
The present invention relates to therapeutic use of anti-TAA antibodies or immunoconjugates, such as antibodies or immunoconjugates against HLA-DR or Trop-2, in combination with one or more drugs, wherein the combination therapy is more effective than the antibody alone, drug alone, or the combined effects of drug and antibody alone. In preferred embodiments, the combination exhibits synergistic effects. In other preferred embodiments, the drugs of use may be ones that induce DNA strand breaks, such as auristatins, colicheamicins, camptothecins (e.g., SN-38) or a prodrug form of 2-pyrrolinodoxorubicine (P2PDox). Exemplary drugs inducing DNA strand breaks include, but are not limited to, SN-38, P2PDox, topotecan, doxorubicin, etoposide, cisplatinum, oxaliplatin, or carboplatin. In alternative embodiments, the drugs of use for combination therapy belong to the categories of microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or phosphoinositide 3-kinase (PI3K) inhibitors. The drugs may be administered separately or together with the antibodies, or may be conjugated to the antibody prior to administration. In the latter case, the antibodies and drugs may be linked via an intracellularly-cleavable linkage that increases therapeutic efficacy. In other alternative embodiments, the antibody may be conjugated to a different drug (such as SN-38) to form an immunoconjugate, and the immunoconjugate may be administered in combination with with a microtubule inhibitor, PARP inhibitor, Bruton kinase inhibitor or PI3K inhibitor. Preferably, immunoconjugates are administered at specific dosages and/or specific schedules of administration that optimize their therapeutic effect. The optimized dosages and schedules of administration of antibody-drug conjugates (ADCs) for human therapeutic use disclosed herein show unexpected superior efficacy that could not have been predicted from animal model studies, allowing effective treatment of cancers that are resistant to standard anti-cancer therapies, including irinotecan (CPT-11), paclitaxel or other compounds that induce DNA strand breaks. Surprisingly, combination therapy with antibody-SN38 immunoconjugates and microtubule inhibitors or PARP inhibitors shows unexpected synergistic effects. In a particularly preferred embodiment, an SN-38 conjugated antibody of use is an anti-Trop-2 antibody, such as IMMU-132 (sacitizumab govitecan, also known as hRS7-CL2A-SN-38 or IMMU-132). More preferably, the methods are of use in treating triple-negative breast cancer (TNBC), metastatic colorectal cancer, SCLC or NSCLC, as well as other Trop-2-expressing cancers. Other SN-38 conjugates, such as with antibodies targeting other cancer-associated antigens, such as CD19, CD20, CD22, CD66e (CEACAM5), CD74, HLA-DR, IGF-1R, folate receptor, and others listed below, also can be synergistically effective, or at least additive without increasing dose-limiting toxicities, when combined with similar classes of drugs. In another preferred embodiment, an anti-HLA-DR antibody of use is a humanized L243 antibody (hL243).
Background of the Invention
For many years it has been an aim of scientists in the field of specifically targeted drug therapy to use monoclonal antibodies (MAbs) for the specific delivery of toxic agents to human cancers. Conjugates of MAbs that target tumor-associated antigens (TAA) and suitable toxic agents have been developed, but have had mixed success in the therapy of cancer in humans, and virtually no application in other diseases, such as infectious and autoimmune diseases. The toxic agent is most commonly a chemotherapeutic drug, although particle-emitting radionuclides, or bacterial or plant toxins, have also been conjugated to MAbs, especially for the therapy of cancer (Sharkey and Goldenberg, CA Cancer J Clin. 2006 July-August; 56(4):226-243) and, more recently, with radioimmunoconjugates for the preclinical therapy of certain infectious diseases (Dadachova and Casadevall, Q J Nucl Med Mol Imaging 2006; 50(3):193-204).
The advantages of using MAb-chemotherapeutic drug conjugates are that (a) the chemotherapeutic drug itself is structurally well defined; (b) the chemotherapeutic drug is linked to the MAb protein using very well-defined conjugation chemistries, often at specific sites remote from the MAbs' antigen-binding regions; (c) MAb-chemotherapeutic drug conjugates can be made more reproducibly and usually with less immunogenicity than chemical conjugates involving MAbs and bacterial or plant toxins, and as such are more amenable to commercial development and regulatory approval; and (d) the MAb-chemotherapeutic drug conjugates are orders of magnitude less toxic systemically than radionuclide MAb conjugates, particularly to the radiation-sensitive bone marrow.
Camptothecin (CPT) and its derivatives are a class of potent antitumor agents. Irinotecan (also referred to as CPT-11) and topotecan are CPT analogs that are approved cancer therapeutics (Iyer and Ratain, Cancer Chemother. Phamacol. 42: S31-S43 (1998)). CPTs act by inhibiting topoisomerase I enzyme by stabilizing topoisomerase I-DNA complex (Liu, et al. in The Camptothecins: Unfolding Their Anticancer Potential, Liehr J. G., Giovanella, B. C. and Verschraegen (eds), NY Acad Sci., NY 922:1-10 (2000)). CPTs present specific issues in the preparation of conjugates. One issue is the insolubility of most CPT derivatives in aqueous buffers. Second, CPTs provide specific challenges for structural modification for conjugating to macromolecules. For instance, CPT itself contains only a tertiary hydroxyl group in ring-E. The hydroxyl functional group in the case of CPT must be coupled to a linker suitable for subsequent protein conjugation; and in potent CPT derivatives, such as SN-38, the active metabolite of the chemotherapeutic CPT-11, and other C-10-hydroxyl-containing derivatives such as topotecan and 10-hydroxy-CPT, the presence of a phenolic hydroxyl at the C-10 position complicates the necessary C-20-hydroxyl derivatization. Third, the lability under physiological conditions of the δ-lactone moiety of the E-ring of camptothecins results in greatly reduced antitumor potency. Therefore, the conjugation protocol is performed such that it is carried out at a pH of 7 or lower to avoid the lactone ring opening. However, conjugation of a bifunctional CPT possessing an amine-reactive group such as an active ester would typically require a pH of 8 or greater. Fourth, an intracellularly-cleavable moiety preferably is incorporated in the linker/spacer connecting the CPTs and the antibodies or other binding moieties.
A need exists for more effective methods of preparing and administering antibody-drug conjugates, such as antibody-SN-38 conjugates, and more effective combination therapy with antibodies or immunoconjugates and drugs, such as microtubule inhibitors, PARP inhibitors, Bruton kinase inhibitors or PI3Ks inhibitors.